RESUMO
Although a few nanomedicines have been approved for clinical use in cancer treatment, that recognizes improved patient safety through targeted delivery, their improved efficacy over conventional drugs has remained marginal. One of the typical drawbacks of nanocarriers for cancer therapy is a low drug-loading capacity that leads to insufficient efficacy and requires an increase in dosage and/or frequency of administration, which in turn increases carrier toxicity. In contrast, elevating drug-loading would cause the risk of nanocarrier instability, resulting in low efficacy and off-target toxicity. This intractable drug-to-carrier ratio has imposed constraints on the design and development of nanocarriers. However, if the nanocarrier has intrinsic therapeutic effects, the efficacy would be synergistically augmented with less concern for the drug-to-carrier ratio. Sunitinib-loaded micellar nanocomplex (SU-MNC) was formed using poly(ethylene glycol)-conjugated epigallocatechin-3-O-gallate (PEG-EGCG) as such a carrier. SU-MNC specifically inhibited the vascular endothelial growth factor-induced proliferation of endothelial cells, exhibiting minimal cytotoxicity to normal renal cells. SU-MNC showed enhanced anticancer effects and less toxicity than SU administered orally/intravenously on human renal cell carcinoma-xenografted mice, demonstrating more efficient effects on anti-angiogenesis, apoptosis induction, and proliferation inhibition against tumors. In comparison, a conventional nanocarrier, SU-loaded polymeric micelle (SU-PM) comprised of PEG-b-poly(lactic acid) (PEG-PLA) copolymer, only reduced toxicity with no elevated efficacy, despite comparable drug-loading and tumor-targeting efficiency to SU-MNC. Improved efficacy of SU-MNC was ascribed to the carrier-drug synergies with the high-performance carrier of PEG-EGCG besides tumor-targeted delivery.
Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Neoplasias Renais/tratamento farmacológico , Nanopartículas/química , Sunitinibe/farmacologia , Chá/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Catequina/análogos & derivados , Catequina/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Portadores de Fármacos/química , Feminino , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Camundongos , Camundongos Nus , Camundongos Transgênicos , Micelas , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Tamanho da Partícula , Polietilenoglicóis/química , Sunitinibe/administração & dosagem , Sunitinibe/química , Propriedades de Superfície , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Nanotransducer-mediated photothermal therapy (PTT) has emerged as an attractive therapy modality against cancer, but its efficacy is often limited by the amount of nanoparticles delivered to tumors. Previous studies showed a vasculature modulation treatment, which dilates or prunes tumor blood vessels, may enhance tumor uptake of nanoparticles. However, exploiting these approaches for improved PTT has seldom been studied. In this study, we investigated the impact of mild hyperthermia or anti-angiogenesis therapy on PTT. Briefly, we gave tumor-bearing balb/c mice low doses of sunitinib or submerged tumors in a 42⯰C water bath. Next, we injected PEGylated reduced graphene oxide (RGO-PEG) and irradiated the tumors to induce PTT. We then followed up the treatment with multi-parameter MRI. Contrary to expectation, both vessel modulation strategies led to diminished PTT efficacy. Our results show that vessel modulation does not warrant improved PTT, and should be carefully gauged when used in combination with PTT.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Neoplasias da Mama/terapia , Hipertermia Induzida , Imageamento por Ressonância Magnética/métodos , Neovascularização Patológica/terapia , Fototerapia , Sunitinibe/administração & dosagem , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Apoptose , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/patologia , Proliferação de Células , Terapia Combinada , Feminino , Grafite/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/administração & dosagem , Nanopartículas/química , Neovascularização Patológica/patologia , Sunitinibe/química , Sunitinibe/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tumor angiogenesis is a key step in the process of tumor development, and antitumor angiogenesis has a profound influence on tumor growth. Herein we report a dual-function drug delivery system comprising a Near-infrared (NIR) dye and an anti-angiogenic drug within liposomes (Lip-IR780-Sunitinib) for enhanced antitumor therapy. The hydrophobic NIR dye IR780 was loaded into the liposome phospholipid bilayer, and the bilayer would be disrupted by laser irradiation so that anti-angiogenic drug sunitinib release would be activated remotely at the tumor site. The released hydrophilic sunitinib could potentially target multiple VEGF receptors on the tumor endothelial cell surface to inhibit angiogenesis. Meanwhile, IR780-loaded liposomes kill the cancer cells by photothermal therapy. Lip-IR780-Sunitinib exhibited enhanced anti-tumor and anti-angiogenic effects in vitro and in vivo. This system facilitates easy and controlled release of cargos to achieve anti-tumor angiogenesis and photothermal therapy.